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Steric and Electronic Effects on an Antibody‐Catalyzed Diels–Alder Reaction
Author(s) -
Gozin Yael,
Hilvert Donald
Publication year - 2002
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200290015
Subject(s) - chemistry , steric effects , thiophene , catalysis , substrate (aquarium) , active site , stereochemistry , diene , photochemistry , computational chemistry , organic chemistry , oceanography , natural rubber , geology
A series of substituted thiophene dioxides was tested as diene substrates for the antibody 1E9, which was elicited with a hexachloronorbornene derivative and normally catalyzes the inverse electron‐demand Diels–Alder reaction between 2,3,4,5‐tetrachlorothiophene dioxide (TCTD) and N ‐ethylmaleimide (NEM). Previous structural and computational studies had suggested that the catalytic efficiency of this system derives in part from a very snug fit between the apolar active site and the transition state of this reaction. Nevertheless, replacing all the Cl‐atoms in the hapten with Br‐atoms leads to no loss in affinity ( K d =0.1 n M ), indicating substantial conformational flexibility in the residues that line the binding pocket. Consistent with this observation, the 2,3,4,5‐tetrabromothiophene dioxide is a good substrate for the antibody ( k cat =1.8 min −1 , K NEM =14 μ M ), despite being considerably larger than TCTD. In contrast, normal electron‐demand Diels–Alder reactions between NEM and unsubstituted thiophene dioxide or 2,3,4,5‐tetramethylthiophene dioxide, which are much smaller or nearly isosteric with TCTD, respectively, are not detectably accelerated. These results show that the electronic properties of the 1E9 active site are optimized to a remarkable degree for the inverse electron‐demand Diels–Alder reaction for which it was designed. Indeed, they appear to play a more important role in catalysis than simple proximity effects.